Herpes simplex virus infects one in five Americans. Genital herpes is characterized by recurrent vesicular or ulcerative lesions of the genitals. Active lesions are a risk factor for sexual transmission of HIV. HSV can be transmitted during primary or recurrent infection, regardless of whether clinical manifestations are present, which puts many unborn children at risk. Neonatal herpetic infections are frequently severe, with a high mortality rate and substantial neurologic impairment in survivors. Currently, no licensed vaccine is available to prevent HSV disease, and recent attempts to demonstrate efficacy of adjuvanted subunit vaccines have failed. An efficacious vaccine would reduce transmission of HSV and consequences of neonatal disease, lower the complication risk associated with preventative cesarean deliveries potentially reduce transmission of HIV and significantly lower associated healthcare costs. The experiments in this phase 1 SBIR proposal utilize recent advances to generate a set of rationally designed HSV-2 recombinants. Building upon previous work with attenuated HSV-1 recombinants, they have removed all, or part of, the internal inverted repeat of HSV-2. In addition, their preclinical studies with live attenuated HSV-2 recombinants have demonstrated that this approach produces protective levels of immunity. A safe, immunogenic live, attenuated vaccine candidate will be selected for further development. Specific aims of the proposed research are 1) create recombinant HSV-2 vaccine strains with modifications of the internal repeat region, 2) identify the region in the internal repeats essential for neurovirulence, and 3) select a neuroattenuated genetically stable virus for vaccine development. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE